Disialoganglioside GD2+ tumors account for ~10% of cancer deaths. Anti-GD2 antibody therapies have shown promise in advanced clinical trials in melanoma, neuroblastoma, and other tumors. However, current antibody approaches suffer from significant neurotoxicity due to binding and complement activation on GD2+ neurons. An antibody (8B6) that recognizes a related antigen, O- acetylated GD2 (OAcGD2), shares many of the beneficial attributes of GD2 antibodies (tumor selectivity, mediates apoptosis, ADCC, effective in anti-tumor mouse models) but does NOT bind to normal neurons. Anti-OAcGD2 8B6 has a lower Kd and is as active in vitro and in vivo as anti-GD2. In addition, 8B6 is more specific than anti-GD2, with no cross-reactivity on nervous tissue. These observations instruct the overall goal of this project to develop a Best-in-Class antibody therapy targeting tumors expressing OAcGD2. In phase I, we will generate a humanized and Fc-enhanced form (eh8B6) of murine anti-OAcGD2 mAb 8B6. We will evaluate binding, specificity, in vitro functional activity, and in vivo anti-tumor activity of eh8B6. This innovative therapeutic humAb will be the safest and most effective treatment for OAcGD2+ tumors. Demonstration of a humAb with a nanomolar Kd, high specificity for OAcGD2, and in vivo anti-tumor activity, will merit submission of a phase II application. Phase II work will focus on obtaining the preclinical data necessary for submission of an IND. Initial CMC work, pharmacokinetics and toxicology, as well as expanded animal studies will be performed.